Test availability at launch can be underestimated, under-budgeted and under-resourced: an example using real-time, real world analysis of PD-L1

May 25th, 2017

Jordan Clark

Diaceutics gave a presentation at TriCON 2017 discussing how biomarkers and diagnostics are still falling short at launch, even though the industry is no longer in its infancy. Here, Jordan Clark, Managing Director, reports on how we can track the real-time, real world development of PD-L1 in NSCLC and highlights the differences in the test’s availability, budgeting and resourcing.

The dynamic PD-L1 space provides opportunities to undertake real-time market analysis and improve our understanding of novel biomarker adoption. It’s an interesting space, too, seeing as in the first 18 months since launch over 70 US labs are using the test, indicating PD-L1 testing has a fast-track pattern of uptake in parallel with treatment recommendations. It’s also in line with ALK and EGFRm – 75% of all NSCLC trials for five PD-1/PD-L1 therapies are likely to require known PD-L1 status, bringing PD-L1 in line with ALK and EGFRm as key disease-based biomarkers. When we combine these facts with the knowledge that the anti PD-1 therapy class of drugs is slated to achieve $33 billion, it is worrying that the PD-L1 testing market is still underdeveloped.

There is an increasing interdependency between therapy and diagnostic that is likely to continue as regulatory authorities around the world encourage joint submissions for approval and support simultaneous launches. In the US we observe that:

$200bn of therapy revenue is already dependent upon the diagnostic ecosystem (42% of all therapy revenue) at each disease level1.

70% of future therapy launches (2020+) will incorporate a diagnostic, making the link with diagnostics a predominant feature of the pharma commercial model1.

Already some $3m per day is being spent across the industry on diagnostic investments to optimize treatment1.

There has been a dramatic increase in biomarker-targeted drug development programs: 5% of new drug approvals were for targeted therapies in the early 1990s rising to 45% in 20132.

PD-L1 testing is a dynamic market that has given Diaceutics a unique opportunity to analyse the availability and adoption of PD-L1 in NSCLC as a real-time, real world example. What we mean by availability is having nearby, trusted laboratories to run the chosen test. Analysis of the PD-L1 market reveals that in less than three years there have been three new entities, six indications, over 16 approvals and more than three tests, and this list was expanded in March 2017 with the approval of Keytruda for cHL and Bevencio for Mercel cell carcinoma.

Within NSCLC, PD-L1 status reveals a competitive component given that around 40 per cent of all NSCLC trials, regardless of the phase (I-IV), require determination of PD-L1 status. However, despite therapy/diagnostic dependency and expected PD-L1 integration, barriers to availability and adoption persist. This is a concern because we know that unaddressed diagnostic need leads ultimately to the loss of potential patients eligible for targeted therapy.

What are the factors affecting availability in the US? Various factors can affect availability including confusion over testing options, interpretation and reporting of results. Our analysis of PD-L1 testing in the US reveals these are some of the questions raised:

Do labs require multiple platforms and could they possibly know what clinicians want to order?

Is PD-L1 comparable between clones?

How shall PD-L1 staining be interpreted and reported?

Should immune cell staining be reported?

Which expression level is meaningful?

Do clinicians need PD-L1 tested?

Do these decisions impact payer decisions to cover testing and a therapeutic?

Another factor affecting availability here is the significant role LDTs play in the provision of PD-L1 testing. Around 50% of labs have only an LDT option, but LDTs are less well-defined with the Ab being used and cut-off values in place. Often labs will offer both LDT and kits but there is no suggestion that LDTs are preferred.

Even though availability of PD-L1 testing has increased since companion diagnostic approval it has always lagged behind. Diaceutics began tracking PD-L1 testing in 2015 and found that test availability already lagged behind 2014 approvals. 2016 saw strong availability of PD-L1 testing but we may also have reached a testing plateau at the end of 2016 in the US, with broad adoption in key laboratories.

Does Europe experience similar issues on availability? The Diaceutics global network of laboratories has enabled us to track particular markets in relation to PD-L1 testing and a focus on Germany and Italy for PD-L1 in NSCLC has provided some contrasting data on availability and investment in these countries3.

Germany: There are ten different antibody clones available for testing here, but early harmonization, driven by pathologists, made the choice of antibodies easier, with heavy adoption of one antibody.

Due to EU legislation, German labs used the harmonization results to improve the availability independently of the platform.

Over 30 training sessions were held in 2016, educating and aiding labs on the validation, interpretation of the results and reporting.

Diagnostic reimbursement was incorporated into the existing system.

Italy: There are four different antibody clones available for testing here and there is still lack of consensus on which should be used; harmonization studies started later.

There is a tendency to adopt the kit corresponding to the existing platform and test adoption is pushed by clinicians.

Fewer than five training sessions were conducted in 2016, mostly based on the platform rather than the test.

Reimbursement coverage is poor and an anatomical pathology lab is necessary to claim reimbursement for PD-L1.

Comparison of PD-L1 testing in practice

Germany

Italy

Top volume NSCLC laboratories performing PD-L1 testing

93%

8%

All NSCLC samples tested for PD-L1

44%

2%

How do availability issues impact physicians? We recognise that availability and adoption – the adoption of the test by physicians for use with recommended patients (as described in guidelines) – can be interdependent. The test needs to be available in labs to facilitate physicians’ choice on testing but if they adopt a particular test above others the availability of other tests can be reduced. Understanding around test differences is improving but prescribers remain unclear and this creates uncertainty for prescribers and impacts their confidence in testing4. Furthermore, pharma companies are sending out different messages, with the 22C3 companion diagnostic being promoted with Keytruda and 28-8 complementary diagnostics promoted with Opdivo.

How do availability issues impact testing and ROI? The availability issues clearly impact return on investment and timely investment will boost the returns. When Diaceutics analysed the differences between the German and Italian markets for the webinar What are the major differences in biomarker test adoption in European countries? An analysis of PD–L1 testing in Italy and Germany, it revealed surprising statistics about Italy in relation to PD-L1 testing:

Loss of treatment opportunities: 1,775 patients NOT treated

Lost revenue opportunity: $194m

Diagnostic investment required: $2m

ROI for every $1 diagnostic investment: $97m

This one example demonstrates that despite prescribing’s increasing dependency on PD-L1 testing, issues of availability and adoption persist. Crucially, 20 years on from Herceptin we still observe the absence of attention to pre-launch market development for critical biomarkers and patients are being missed. (More information will be made available after our bottom up analysis of patients lost to anti PD-1 treatment directly caused by testing issues is completed in May 2017.)

Summary An increasing requisite for PD-L1 status knowledge prior to prescribing will drive increased outcomes and response rates with PD-L1 therapies but guidelines clarifying PD-L1 testing and reporting are lagging behind the dynamic testing landscape. Several factors however, including early physician confusion and a lack of standardization in testing and reporting, will continue to hinder test availability. A comprehensive biomarker strategy is key to a successful therapeutic launch and increasingly impacts return on investment but current planning and implementation on the majority of biomarkers is underestimated, under-budgeted and under-resourced

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